CN104956223A - Trimethylamine-n-oxide as biomarker for the predisposition for weight gain and obesity - Google Patents
Trimethylamine-n-oxide as biomarker for the predisposition for weight gain and obesity Download PDFInfo
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- CN104956223A CN104956223A CN201380071702.2A CN201380071702A CN104956223A CN 104956223 A CN104956223 A CN 104956223A CN 201380071702 A CN201380071702 A CN 201380071702A CN 104956223 A CN104956223 A CN 104956223A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B5/00—Measuring for diagnostic purposes; Identification of persons
- A61B5/48—Other medical applications
- A61B5/4869—Determining body composition
- A61B5/4872—Body fat
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/04—Endocrine or metabolic disorders
- G01N2800/044—Hyperlipemia or hypolipemia, e.g. dyslipidaemia, obesity
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/50—Determining the risk of developing a disease
Abstract
The present invention relates generally to the field of nutrition and health. In particular, the present invention relates to a new biomarker, its use and a nnethod that allows it to diagnose the likelihood to resist diet induced weight gain, and/or to be susceptible to a diet induced weight gain. For example, the biomarker may be trimethylamine-N-oxide.
Description
Relate generally to nutrition of the present invention and health field.Especially, the present invention relates to neoformation mark, its purposes and allow the weightening finish of its diagnosis opposing diet induced, and/or be subject to the method for possibility of weightening finish of diet induced.Such as, biomarker can be trimethylamine-N-oxide.This biomarker also can be used for the impact of diagnose/monitor lifestyle change on the risk that increases weight in object.
Obesity has become most important global health problem in 21 century, because it increases trouble other diseases, comprises the risk of diabetes B, hepatic steatosis (NAFLD), cancer, arthritis and angiocardiopathy (CVD).Fat aetiology interacts from h and E factor such as high caloric diet, the complexity that lacks physical exertion and behavior.The intestinal microbiota participating in the different physiological roles such as maturation of enteron aisle innate immune system and the digestion/absorption of nutrient also have impact on the development of several metabolic disease and seems to have significant impact to obesity.Therefore, there is fat individuality tendency different according to these multifactor reasons.
Take in the uneven diet being rich in fat and/or carbohydrates to preserve speed with the triglyceride of the increase in adipose tissue and lean tissue mass such as liver, muscle and heart and be associated.This ectopic fat deposition inductivity Fatty toxicity is also associated with multiple metabolic disorder such as hypertriglyceridemia, hypertension, high fasting blood glucose and insulin resistance (IR).But some are overweight or obese people may develop multiple metabolic disorder and other people keep fit.Such as, the development of the positioning effects metabolic disorder of fat deposition in health.Discharge atherogenic adiponectin by being enough to and the epicardial fat processing fatty acid is associated with people's cardiovascular disease (CVD) mark clearly.Under comparing, intrahepatic fat is associated with inflammation and insulin resistance.The metabolic activity that the people such as Wildman also highlight the difference of race in healthy female middle-aged and group difference and internal organ and subcutaneus adipose tissue is associated, this fat relevant with the group of CVD tendency that can interfere with the development out.Therefore, the stage identifies the possibility of the fat relevant metabolic disorder of development in early days, is relevant to evaluate the development of individual metabolism state and preventing metabolic diseases effectively.
Therefore for this area provide allow early stage-ideally before its weightening finish-method of object that qualification is probably increased weight when the rich fatty diet of consumption will be desirably.
Should not be considered to admit that this type of prior art is extensively known or form the part of common general knowledge in this area to any reference of prior art file in this instructions.
The object of the invention is to improve art technology and provide permission effectively people to be layered as it in early days in particular and whether probably respond high fat diet and the method that increases weight.
The present inventor surprisingly finds that object of the present invention can be realized by the theme of independent claims.Dependent claims has further developed viewpoint of the present invention.
Therefore, the invention provides biomarker, the method for the possibility of the weightening finish of its purposes and diagnosis opposing high fat diet induction.
As used in this specification, word " comprises ", " containing ", should not explain with similar word with exclusiveness or exhaustive implication.In other words, it is intended to mean " including, but are not limited to ".
The present inventor has employed metabolism group method to realize object of the present invention.Metabolism group is considered to the systems approach of the perfect foundation characterizing metabolic phenotype in today, it comprises many factors such as environment, medicine, diet, life style, science of heredity, and the impact of microorganism group factor.The gene expression of possibility change from prompting physiology is different with proteome data, metabolin and in cell, tissue and intraorganic dynamic concentration change, represents the real terminal of physiological regulating control process.
Therefore, research changes with the metabolism gradually that multiple Diet intervention associates with disease progression is suitable method.Recently, the discovery based on metabolism group and lipidomics has accelerated our understanding to lysis, and by the prevention of subclinical illness that is provided for being associated with metabolic syndrome and the new way of Nutrition Management." group is learned " data have highlighted energetic supersession (Krebs circulation), lipid and amino acid processing, and inflammatory signal is to contribution that is fat and IR outbreak.
Use collect in time urine samples proton magnetic resonance (PMR) (
1h NMR) combination of spectroscopy and weightening finish monitoring, the present inventor identifies the new metabolism biological marker increased weight gradually of being induced by high fat diet in the C57BL/6 mouse model of good definition.This animal model known shows extreme phenotype in homogenic animal, namely resist or tend to higher fatty acid induction weightening finish distribution animal.The present inventor has characterized the short-term (7 days) of the C57BL/6 mouse fed with high fat diet (HFD) and long-term (60 days) metabolic adaptability and has established the concrete metabolic indicator that the phenotypic variability in the mouse (namely resisting or tend to the animal of weightening finish of higher fatty acid induction) fed with HFD is associated.By using metabolism group method, inventor display line plastochondria metabolic pathway (fatty acid beta oxidation, branched-chain amino acid kalabolism, butyric acid metabolism, nicotinamide adenine dinucleotide approach and Krebs circulation) to be fed fast upregulation by higher fatty acid nicotinamide adenine dinucleotide Krebs, and this may reflect the infringement of the saturated and energetic supersession of mitochondrial fatty acid.
The mouse of inventor's fat resistance under can being presented at HFD is associated with the concrete activation of mitochondrial oxidation pathways (beta-oxidation, butyric acid metabolism and leucine kalabolism), and described activation may be the protective mechanism for fatty acid overload.
These results highlight mitochondria in the developing effect of obesity and allow to draw such conclusion, that is, use the concrete biomarker group that inventor has identified, can measure development metabolic disorder, such as fat possibility from early stage metabolic indicator.
Inventor can be presented at the higher fatty acid urine metabolism response of (the 7th day) after a week of feeding and make to predict the final weightening finish (the 60th day) of each individuality, can also according to its opposing or tend to higher fatty acid induction weightening finish tendency and to animal layering.
Therefore, the present invention relates to new biomarker trimethylamine-N-oxide.
The invention still further relates to trimethylamine-N-oxide as in urine for detecting and/or quantitatively resist the purposes of biomarker of the possibility of the weightening finish of high fat diet induction.Similarly, the invention still further relates to trimethylamine-N-oxide as in urine for detecting and/or be quantitatively subject to the purposes of biomarker of possibility of weightening finish of high fat diet induction.
The invention still further relates in diagnosis experimenter the method for the possibility of the weightening finish of resisting high fat diet induction, described method comprises the level measuring previously trimethylamine-N-oxide from the urine samples that experimenter to be tested obtains, with the trimethylamine-N-oxide level comparing experimenter and the reference point measured in advance, wherein the pre-reference point measured is based on the average trimethylamine-N-oxide level in urine in control population, and the trimethylamine-N-oxide level wherein increased in the pre-reference point sample measured or shortage change the possibility of the reduction showing the weightening finish of resisting high fat diet induction.Similarly, the present invention also relates to diagnose in experimenter the method for the possibility of the weightening finish being subject to high fat diet induction, described method comprises the level measuring and previously obtain trimethylamine-N-oxide urine samples from experimenter to be tested, and compare the trimethylamine-N-oxide level of experimenter and the reference point measured in advance, wherein the pre-reference point measured is based on the average trimethylamine-N-oxide level in urine in control population, and the trimethylamine-N-oxide level prompting wherein reduced in the pre-reference point sample measured is subject to the possibility of the reduction of the weightening finish of high fat diet induction.
This biomarker of the present invention also can be used for diagnosis and/or monitors living-pattern preservation to the impact of the risk that increases weight in experimenter.For this, biomarker level can be measured before lifestyle change and after lifestyle change, the level of acquisition can be compared with the level of described biomarker.
Fig. 1: the variability of body gains in the colony of n=56 the mouse of the HFD that feeds.(A) experimental design.(B) 7 days and 60 days HFD feed after the body weight distribution of mouse.(C) identify fat non-response person (NR) and strong respondent (SR) mouse at each time point.Some NR and SR mouse are observed at 2 time points or in the whole process of experiment.(D) after 7 days that before diet, (t0), HFD raise (t1) and after 60 days (t2), contrast (n=24), NR (n=30), and the body weight of SR (n=29) mouse is monitored.S (n=is average ± standard error, and the p value * <0.05 of nonparametric Mann and Whitney inspection, * * <0.001, * * * <0.0001.)
Fig. 2: diet conversion latter 7 days and 60 days, the mouse that C57BL/6HFD feeds or LFD feeds
1h NMR urinates metabolism spectrum.(A) urine of the mouse that the mouse fed from LFD or (B) HFD feed average
1h NMR spectrum.(C) 7 days time LFD and the HFD mouse fed the OPLS-DA score chart of urine metabolism spectrum.(D) 60 days time LFD and the HFD mouse fed the OPLS-DA score chart of urine metabolism spectrum.(E) the hotspot graph display obtained from OPLS-DA coefficient figure finds metabolins significantly different the mouse fed at HFD and LFD.The correlation of metabolin is shown by color code.(red gradient: the positively related metabolin of the mouse fed with HFD and blue gradient: the metabolin of negative correlation).
Fig. 3: NR and the concrete metabolic indicator of SR mouse.(A) from the urine of NR mouse or (B) SR mouse
1h NMR spectrum mean value.(C) 7 days time and (D) 60 days time NR and the OPLS-DA score chart of urine metabolism spectrum of SR mouse.(E) the hotspot graph display obtained from OPLS-DA coefficient figure finds metabolins significantly different NR and SR mouse.The correlation of metabolin is shown by color code.(red gradient: with the positively related metabolin of SR mouse and blue gradient: the metabolin of negative correlation).
The mapping of the homaluria type of the metabolin related in Fig. 4 a and b:BCAA, butyric acid, nicotinamide adenine dinucleotide metabolism, Krebs circulation and beta-oxidation.The integration of average ratio the 7th day to the 0th day or the 60th day to the 0th day with standard error of bar graph display metabolin.The mean value (arbitrary unit) of Y-axis prompting LF, HF, NR and SR mouse.Significant difference between the average ratio of LF and HF or NR and SR uses nonparametric Mann Whitney inspection to calculate: * <0.05, * <0.001, * * <0.0001 (mean value, standard error and p value are in supplementary table 3 and 4).Indirect metabolic reaction is given prominence to dotted arrow.
Fig. 5 be presented at prediction NR and SR in metabolin importance and robustness, as analyzed by random forest assess.
Table 1: the summary of the relation in the weightening finish of higher fatty acid induction between metabolin and weightening finish
Table 2: the summary of the metabolin selected in (SR) individuality multiple over time that increases weight in opposing weightening finish (NR) and tendency
The present invention partly relates to biomarker, and wherein biomarker is trimethylamine-N-oxide.
In experiment described herein, showing trimethylamine-N-oxide in urine with the mouse that HFD feeds increases in time.Do not wish to be bound by any theory, inventor think at present HFD mouse urine in the increase of end-product of some Krebs intercycle things and nicotinamide adenine dinucleotide approach can be considered to the evidence of the excessive generation of energy in mitochondria.Think that the long-term increase of mitochondrial oxidation approach is harmful for mitochondria, cause the infringement of oxidative pathway and energetic supersession.In addition, excessive free fatty acid can be stored in adipose tissue and lean tissue mass as triglyceride, and this can promote organ dysfunction and metabolic disease such as hepatic steatosis or angiocardiopathy.
Inventor has been found that trimethylamine-N-oxide can as the biomarker in body fluid for detecting and/or quantitatively resist the possibility of the weightening finish of high fat diet induction.Body fluid can be urine.Namely it can regularly, non-invasively and obtain under the support not having medical worker to use urine to have such advantage as body fluid.
At this diagnostic method of the external enforcement of human or animal.Usually, previous available from the humoral sample of experimenter to be tested in carry out biomarker detection and/or quantification steps.
Although the present invention is described in the angle of the possibility of the weightening finish of quantitatively opposing high fat diet induction, those skilled in the art should know that identical method also can be used for quantitatively to the possibility of the weightening finish sensitivity of high fat diet induction.If those skilled in the art understand the possibility of the increase of the weightening finish of the level prompting opposing high fat diet induction of the increase of biomarker, the possibility of level prompting to the weightening finish sensitivity of high fat diet induction of the reduction of biomarker increases, and vice versa.
Therefore the present invention also relates to trimethylamine-N-oxide as in urine for detect and/or quantitatively to the purposes of the biomarker of the possibility of the weightening finish sensitivity of high fat diet induction.
The present invention also relates to diagnose experimenter to resist the method for the possibility of the weightening finish of high fat diet induction, described method comprises the level measuring previously trimethylamine-N-oxide from the urine samples that experimenter to be tested obtains, with the trimethylamine-N-oxide level comparing experimenter and the reference point measured in advance, wherein the pre-reference point measured is based on the average trimethylamine-N-oxide level in urine in control population, and the possibility of the increase of the weightening finish of the trimethylamine-N-oxide level prompting opposing high fat diet induction wherein reduced in the pre-reference point sample measured.
The present invention also relates to diagnosis experimenter to the method for the possibility of the weightening finish sensitivity that high fat diet is induced, described method comprises the level measuring and previously obtain trimethylamine-N-oxide urine samples from experimenter to be tested, with the trimethylamine-N-oxide level comparing experimenter and the reference point measured in advance, wherein the pre-reference point measured is based on the average trimethylamine-N-oxide level in urine in control population, and the possibility that the susceptibility of trimethylamine-N-oxide level prompting to the weightening finish of high fat diet induction wherein reduced in the pre-reference point sample measured increases.
Use urine to have such advantage as sample, namely it can use the good method set up non-invasively to obtain.Then outside health, carry out actual diagnostic method.
Can by the level of trimethylamine-N-oxide in any tool detection as known in the art also quantitative sample.Such as, can use
1h-NMR, mass spectrum, such as, UPLC-ESI-MS/MS.Also additive method can be used, such as other spectrographic techniques, chromatographic process, labelling technique or quantitative chemical method.Ideally, by the trimethylamine-N-oxide level in identical method working sample and reference point.
The reference point of pre-mensuration can based on the average trimethylamine-N-oxide level in the body fluid tested in control population.Control population can be have similar genetic background, age and average health status at least 3, preferably at least 10, the more preferably group of at least 50 people.
The present invention allows, such as, in early days, before its weightening finish can cause health risk, to experimenter's layering.By knowing the impact of the weightening finish whether being subject to high fat diet induction, can correspondingly adjust life style and diet in early days.Suitable life style, ideally with personalized nutritional programs, allows to maintain healthy physique and avoids to make in caloric restriction and/or motion scheme and significantly make great efforts to regain this healthy physique.
Although trimethylamine-N-oxide is the effective instrument of diagnostic method of the present invention as unique mark, if diagnosis depends on more than only a kind of mark, quality and/or the predictability strength of described diagnosis will be enhanced.
Therefore can combinationally use one or more other marks with trimethylamine-N-oxide, one or more other marks described are for diagnosing the possibility of the increase of the weightening finish of opposing high fat diet induction and/or for diagnosing the possibility of increase of the weightening finish sensitivity to high fat diet induction.
What inventor was surprised see also can use other biological mark with detect the increase of the weightening finish of opposing high fat diet induction possibility and/or for diagnosing the possibility of the increase of the weightening finish sensitivity to high fat diet induction.
Inventor like this has identified the urine concentration of increase of hexanoyl glycocoll, isovaleryl glycocoll, leucine, isobutyrate, acetate, and the concentration of the reduction of glycocyamine salt, sucrose, tartrate, hippuric acid and hydroxyphenyl acetoglycocoll allows the possibility of the increase of the weightening finish of diagnosis opposing high fat diet induction.
Therefore, method of the present invention also can comprise the following steps: measure in urine samples and be selected from hexanoyl glycocoll, isovaleryl glycocoll, leucine, isobutyrate, acetate, glycocyamine salt, sucrose, tartrate, the level of at least one other biological mark of hippuric acid and hydroxyphenyl acetoglycocoll, and compare the level of at least one other biological mark of experimenter and the reference point measured in advance, wherein the pre-reference point measured is based on the average level of this at least one other biological mark in the urine samples of normal health control population, and wherein in urine samples than the hexanoyl glycocoll of the increase of the pre-reference point measured, isovaleryl glycocoll, leucine, isobutyrate, the glycocyamine salt of acetate and/or reduction, sucrose, tartrate, the possibility of the increase of the weightening finish of hippuric acid and/or hydroxyphenyl acetoglycocoll level prompting opposing high fat diet induction.Therefore, than hexanoyl glycocoll, isovaleryl glycocoll, leucine, isobutyrate, the acetate of the reduction of the pre-reference point measured in urine samples, and/or the prompting of the glycocyamine salt increased, sucrose, tartrate, hippuric acid and/or hydroxyphenyl acetoglycocoll level is to the possibility of the increase of the weightening finish sensitivity of high fat diet induction.
Also can pass through
1h-NMR or mass spectrum, such as, UPLC-ESI-MS/MS detects and quantitative other biological mark.Also additive method can be used, such as other spectrographic techniques, chromatographic process, labelling technique or quantitative chemical method.
Ideally, by whole the evaluated biomarker of identical technological assessment.They can evaluate simultaneously.
Method of the present invention can comprise evaluation at least 2, at least 3, at least 4, at least 5, at least 6 or at least 7 kinds of biomarkers.
Such as, trimethylamine-N-oxide can be evaluated jointly with trimethylamine-N-oxide.
Trimethylamine-N-oxide also can be evaluated with isovaleryl glycocoll jointly.
Trimethylamine-N-oxide also can be evaluated with leucine jointly.
Trimethylamine-N-oxide also can be evaluated with acetate jointly.
Trimethylamine-N-oxide also can be evaluated with trimethylamine-N-oxide and isovaleryl glycocoll jointly.
Trimethylamine-N-oxide also can be evaluated with trimethylamine-N-oxide, isovaleryl glycocoll and leucine jointly.
Trimethylamine-N-oxide also can be evaluated with trimethylamine-N-oxide, isovaleryl glycocoll and acetate jointly.
Trimethylamine-N-oxide also can be evaluated with trimethylamine-N-oxide, isovaleryl glycocoll, acetate and leucine jointly.
Trimethylamine-N-oxide also can be evaluated with trimethylamine-N-oxide, isovaleryl glycocoll, acetate, leucine and glycocyamine salt jointly.
Trimethylamine-N-oxide also can be evaluated with hexanoyl glycocoll, isovaleryl glycocoll, acetate, leucine, glycocyamine salt and hippuric acid jointly.
The advantage evaluated more than a kind of biomarker is to evaluate more biomarkers, and diagnosis will become more reliable.If such as, show concentration as above more than 1,2,3,4,5,6 or 7 kind of biomarker and rise or reduce, then detect and/or quantitatively opposing and/or stronger to the predictability strength of the possibility of the weightening finish sensitivity of high fat diet induction.
Preferably use for characterizing the reference point measuring trimethylamine-N-oxide and optionally other biological mark available from the trimethylamine-N-oxide of tested object and the identical unit of the level of optionally other biological mark.Therefore, if the level of trimethylamine-N-oxide and optionally other biological mark be absolute value such as in the trimethylamine-N-oxide unit of μm ol/l (μM), the reference point in the individuality of the general groups of experimenter or the control population of selection is also based in the trimethylamine-N-oxide unit of μm ol/l (μM).
In addition, reference point can be single cutoff value, such as median or average.The reference point of trimethylamine-N-oxide and optionally other biological mark in the humoral sample obtained, such as average level, Median levels, or " blocking " level, can by measuring a large amount of sample of the individuality in the colony of general groups or selection and Using statistics model such as predicted value method is set up, described predicted value method is for selecting positive criteria or defining recipient's performance curve of optimum specificity (the highest true negative rate) and sensitivity (the highest True Positive Rate), as Knapp, R.G., and Miller, M.C. (1992) .Clinical Epidemiology and Biostatistics.William and Wilkins, Harual Publishing Co.Malvern, Pa. described in, it is incorporated to herein by reference.
One skilled in the art will know that and how to give correct reference point because it is with such as, sex, race, gene genetic, health status or age and change.
In the method for the invention, the possibility prompting of resisting the reduction of the weightening finish of high fat diet induction develops the possibility to overweight and/or fat relevant illness.
" overweight " is defined as adult and has BMI between 25 and 30." body mass index " or " BMI " mean in the weight of kg divided by the height calculated with rice square ratio." obesity " is such patient's condition, is wherein stored in animal, the point that the mortality ratio that particularly people and the natural energy deposit in the adipose tissue in other mammals are increased to the patient's condition healthy with some or increase is associated." obesity " is defined as adult and has the BMI being greater than 30.
The illness be associated with overweight and/or obesity can be that cardiac metabolism disease and/or metabolism go.
Method of the present invention allows it such as to measure the neurological susceptibility degree of experimenter to the weightening finish of diet induced.Therefore whether at present this method can allow the possibility increased weight based on the higher fatty acid-diet of high heat-particularly according to patient to triage, independent of its shortage in weight, normal, overweight or fat.If adult has the BMI being equal to or less than 18.5, be so considered to underweight.
Method of the present invention also can be implemented in shortage in weight, normal, overweight or obese subjects.Especially in shortage in weight, overweight or in obese subjects, method of the present invention can help the genetic predisposition disclosing experimenter.Base thereon-and further consider its general health status and life style-personalized nutritional programs can be developed ideally, it can help maintain or regain health status.
Method of the present invention is not limited to people.It also can use in animal, such as companion animals.Companion animals can be analyzed, such as cat or dog.Base can design nutritional programs thereon, and it will contribute to companion animals good health and a long life.
The research presented in the application provides the cognitive of the physiological mechanism relating to the obesity development that HF (higher fatty acid) induces and highlights the concrete metabolic adaptability be associated with obesity phenotype variability especially.Higher fatty acid picked-up causes quick with the consistent rise of Metabolism of Mitochondria approach, causes the mitochondrial fatty acid of more multi-energy production and increase saturated.In the mouse that HF feeds, identify (NR) mouse that opposing is fat, it activates specific Metabolism of Mitochondria approach (beta-oxidation, butyric acid metabolism and leucine kalabolism) especially and seems to maintain energy homeostasis (Krebs compared with LFD circulate activity).The specific activation of the result of inventor therefore indication wire plastochondria oxidisability approach may make it possible to keep energy homeostasis and protective wire plastochondria from the overloading of fuel.Therefore, mitochondria is seemingly crucial in the developing effect of fat and relevant metabolic disorder.Therefore, the new and prospect likely provided for weight management plan and personalized Nutritional solutions is comprehensively analyzed to this of mechanism forming the basis that the heterogeneity of feeding to HFD adapts to.
Therefore, if method of the present invention allow the possibility-of the reduction of the weightening finish of qualification opposing high fat diet induction or be subject to high fat diet induction weightening finish increase possibility-this can point out the specific activation lacking mitochondrial oxidation approach.
On the contrary, if method of the present invention allow the increase of the weightening finish of qualification opposing high fat diet induction possibility-or to the reduction of the weightening finish sensitivity of high fat diet induction possibility-this can the specific activation of indication wire plastochondria oxidisability approach.
Mitochondrial oxidation approach can be selected from beta-oxidation, butyric acid metabolism and leucine kalabolism.
Because method of the present invention allows the symptom to experimenter's layering without the need to having procatarxis visible, it is for such as children and adolescents, young man and/or be in that to develop overweight or fat experimenter be applicable.
By perceiveing, this type of risk suitably can be tackled and can eliminate in life afterwards and be derived from overweight or fat possible risk in diet and life style.
Therefore, this method can be used for for the group of concrete experimenter designs the diet of layering or designs personalized diet for concrete experimenter.
It will be appreciated by those skilled in the art that they freely can combine whole feature of the present invention disclosed herein.Especially, can with Combination of Methods of the present invention and vice versa for the feature described by purposes of the present invention.In addition, can combine for the feature described by different embodiments of the present invention.
Although the present invention is described by the mode of example, is to be understood that and can carries out modification and modification and not deviate from scope of the present invention as defined in the appending claims.
In addition, when there is the known equivalent of specific features, as specifically quoted in this manual, this type of equivalent is incorporated to.Other advantages of the present invention and feature are apparent from accompanying drawing and non-limiting example.
Embodiment:
Animal handling procedure and sample preparation:
Test under suitable national guidelines at Nestle Research Center (NRC, Switzerland).Maintain and mouse of arbitrarily feeding in whole experimentation under the Light-Dark scheme of 12h-12h in independent cage.Amount to 80 C57BL/6 mouse first accept standard C HD (baseline 3437) for time some weeks and herein after reason (t0) first time of carrying out urinating collect.Then be divided into by mouse 2 groups: 24 different CHD of mouse (low fat D12450B forms see supplementary accompanying drawing) to feed, wherein the ratio of protein, microorganism, mineral matter and carbohydrates is different from the first standard diet.Another 56 mouse HFD feed (higher fatty acid D12492), and wherein diet composition is except carbohydrates and fatty level, can be suitable with second group of CHD.These two groups are characterized by control group and DIO group respectively.Again, 7 days (t1) are changed and 60 days (t2) collects urine samples afterwards at diet.By whole sample quick-frozen in-80C until analyze.Also at t0, t1, t2 to whole mouse weights to monitor the weightening finish in HFD and control group.The difference of HFD and LFD and NR and SR in weightening finish is by non-parametric test (Wilcoxon-Mann-Whitney U checks) assessment.Also food absorption (FI) of every mouse is recorded at t1 and t2.The mouse that the FI of the mouse that HFD feeds feeds than LFD significantly reduces in time.SR mouse also all has the FI higher than NR mouse at two time points.The difference of FI between calculating group is checked by Wilcoxon-Mann-Whitney U.
1h NMR spectrum
By the urine of 40 μ l volumes at the 20 μ l buffer solution (NaHPO containing sodium azide (3mM) and TSP (0.5mM)
4, 0.6M pH=7) and middle dilution.After centrifugation, by using syringe needle to be shifted in 1.7mm diameter NMR pipe by sample.Then by implementing 64 scannings with the standard sequence of 64k data point, record on 600.13MHz spectroscope
1h NMR spectrum.The temperature that NMR tests is maintained 300K.By the process using software TOPSPIN 2.0 (Bruker Biospin, Rheinstetten, Germany) to carry out urinating spectrum.For each spectrum, before being converted into spectrum by Fourier transform instrument, the exponential function broadening by the line corresponding to 1Hz doubles FID.Then manual correction spectrum phase and baseline.By using the chemical shift of TSP signal calibration at δ 0.By using STOCSY (Statistical TOtal Correlation SpectroscopY), spectra database and disclosed distribution realize spectrum and distribute.
Data processing and multivariate data analysis:
Spectroscopic data (from δ 0.2 to δ 9.5) finally inputs Matlab software (version, the mathworks Inc, Natwick MA) and is converted into 22K data point.Water resonance peak (δ 4.7-5.05) is shifted out to eliminate the variability be associated with water resonance presaturation from each spectrum.Then normalization on the total area
1h NMR spectrum and by use " unit variance " convergent-divergent apply different Multivariate Statistics (PCA, OPLS and OPLS-DA).Use reply convergent-divergent (back-scaling) method can show OPLS regression coefficient.In this way, we can estimate the ratio of the variance of each NMR variable of the group difference in responsible model.Build thermal map that display has a metabolin of the highest coefficient value and provide simply comparing of short distance that HFD is fed and long-range metabolism response.Thermal map is generated by the value obtaining the related coefficient of the metabolin distinguishing HFD/LFD or SR/NR.The related coefficient (according to the covariance value gradient in often kind of metabolin from redness to blueness) of cutoff value higher than 0.3 is shown by color diagram.Therefore thermal map provides for the short distance of obesity development and simply comparing of long-range metabolism response.
Univariate data
To the intermediate metabolites from beta-oxidation, BCAA oxidation, Krebs circulation and nicotinamide adenine dinucleotide approach that spectrally can distribute at urine 1H NMR carry out integration with assessment in LFD, HFD, NR and SR group after diet changes 7 days and 60 days the homaluria of these metabolins.For often kind of metabolin, with the integration at 7 days and 60 days places divided by the integration of the 0th day (in pre-intervention process in period) with the homaluria according to these metabolins of baseline normalization.Use nonparametric Mann and Whitney inspection in each time point ratio that more often kind of metabolin obtains between LFD, HFD, NR and SR group.
Main discovery and bright spot:
The weightening finish variability of feeding in the C57BL/6J mouse of HFD.
In order to study the contribution that diet develops obesity, to feed 60C57BL/6J mouse with feed (CHD) during the pre-intervention period of 1 week, carry out diet conversion afterwards and wherein use LFD (n=20) or HFD (n=40) to feed mouse 60 days.Measurement body weight (Fig. 1 .A) in 7 and 60 days during pre-intervention period and after diet replacing.The remarkable weight that Weight Watcher shows the mouse fed than LFD in the mouse that in whole experiment, HFD feeds increases.Especially, HFD feeds the average weight of mouse than control mice height 1.5g (p=3.9x10 7 days time
-7) and 60 days time height 4.5g (p=2.36x10
-8).Strong heterogeneity (coefficient of variation CV=0.05) when weight distribution also reveal that 7 days between HFD group, this even more merited attention (CV=0.120) (Fig. 1 .B) 60 days time.This observes the existence that highlights strong phenotypic variability in HFD group and the existence of concrete metabolic indicator that joins of prompting and these fat sub-phenotypic correlations.
In order to characterize " strong respondent (SR) " and " non-response person (NR) " that feed to HF, we feed 7 days and 60 days according to HF after body gains (BWG) to mouse population layering.Consistently BWG distribution first three/mouse of mono-and rear 1/3rd called after NR and SR mouse respectively, exception is the first half that 3 SR mouse distribute at BWG 60 days time.Select this threshold value to obtain enough samples (NR mouse n=10SR mouse=14) and carry out strong statistical test and identify the significant difference in the metabolic indicator between these two groups in each group.The mouse that NR, SR and LF feed average weight track in time (Fig. 1 .D) discloses SR mouse in experimentation and obtains significantly more weight than the mouse that NR mouse and LF are fed.Interestingly, 7 days time, between NR group and LFD group, body weight does not have significant difference (p=0.10), but significant difference (p=7.67x10 when we identify 60 days in body weight
-5).In addition, the body gains track (regression coefficient=3.85) of NR mouse is similar to the mouse that LF feeds, and the weightening finish behavior and the LF mouse that highlight NR mouse are in time suitable, and SR mouse tends to accumulate weight quickly.This early stage and lasting deflection of body gains track, defines the subgroup of strong respondent and non-response person, points out the procatarxis of the difference that there is the obesity (DIO) to diet induced in C57BL/6J mouse.Therefore, we will test the ability predicting in the mouse that HFD feeds the track that increases weight based on early stage metabolism spectrum in this research.
Urine metabolism notation points out the metabolic indicator continued be associated with the obesity of higher fatty acid induction
In order to study the concrete metabolic indicator developing with the obesity of diet induced and be associated, we use
1h NMR spectrum, before diet gets involved 1 week, obtains urine metabolism spectrum (Fig. 2 .A, 2.B) in 7 and 60 days afterwards.Then by using OPLS-DA model to compare the urine metabolism spectrum of the mouse that LF and HF feeds at each time point.Each model is calculated by using a predictability and several orthogonal components.Pass through R
2y and Q
2y goodness of fit statistics measures the optimum number of orthogonal components.When 7 days (Fig. 2 .C) and 60 days time (Fig. 2 .D) model the display of OPLS-DA score chart highlight along predictability component (Tpred) the strong metabolism that is associated of feeding with HF and make a variation and illustrate that the second axle of the first orthogonal components (Torth) reflects simultaneously and organize the interior variability be associated with the effect not relying on diet.
For often kind of model, qualification also summarizes the metabolin with the highest related coefficient in thermal map (Fig. 2 .E), the urine metabolism variation between described thermal map prompting LF and HF mouse.Specifically, when 7 days and 60 days in HF group, carnitine, hexanoyl glycocoll, and the level of the intermediate (isovaleryl glycocoll, α-one-β methylvaleric acid and α-one-valeric acid) of BCAA oxidation significantly increases.On the contrary, in whole experimentation in HF group from microorganism choline metabolism produce methylamine derivative (trimethylamine (TMA), and trimethylamine-N-oxide (TMAO)) and by enteric bacteria, the level of the end-product (phenylacetylglycine) of degrading aniline is reduced.Especially, between 7 days and 60 days TMAO urine level in degree of variation pointed out and moved at the feed time dependence of conversion of lower TMA to TMAO of HFD.Therefore, HFD treatment can imply the remarkable change of intestinal microbiota activity.The time dependence metabolic adaptability that HFD feeds also is characterized by the remarkable reduction of indoxyl sulfate in the urine of the HF mouse of 7 days of feeding.The end-product (N1-methyl-2-pyridone-5-formamide: 2PY and N1-methyl-4-pyridone-3-formamide: 4PY) of nicotinamide adenine dinucleotide (nicotinamide adenine dinucleotide) approach also with the HF mouse positive correlation of 60 days of feeding.In the group that in the group that HFD feeds, the excretion of isovaleryl glycocoll, α-one-Beta-methyl valeric acid and KIV is fed than LFD in time significantly and as one man increase, the qualitative and stable candidate biomarker thing of DIO is thus which constituted.
The urine metabolism notation of NR and SR mouse highlights with lipophilia and resists the concrete metabolic adaptability that obesity phenotype is associated
The foundation of the metabolism spectrum of SR and NR mouse makes it possible to identify and the metabolin that the highest divergence in weightening finish is associated.Pairing OPLS-DA model is used to carry out between NR and SR when 7 days and 60 days
1the comparison (Fig. 3 .A, 3.B) of H NMR spectroscopic data.At 7 days (Fig. 3 .C), and time 60 days (Fig. 3 .D), OPLS-DA score chart illustrated good distinguishing between predictability component (Tpred) NR and SR mouse.Second axle describes the orthogonal variation to the response that strong obesity is associated.Interestingly, before diet is changed, do not identify the difference in the urine metabolism spectrum of NR and SR mouse, this highlights when all having similar phenotype and metabolic pattern with C57BL/6J mouse during diet.
Summarize the difference metabolism that during the thermal map (Fig. 3 .E) of metabolin that participation group is separated illustrates the short distance of feeding at HF, during (7 days) and long-range, (60 days) are associated with NR and SR mouse to compose.Especially, relate to leucine kalabolism, concrete metabolic indicator that beta-oxidation and SCFA are produced is associated with the classification of obesity.In fact, hexanoyl glycocoll, isovaleryl glycocoll, leucine, acetate and isobutyrate and SR mouse negative correlation in whole experimentation.Because these marks are unanimously lowered in SR mouse, they constitute the stable candidate markers of opposing obesity phenotype.7 days and 60 days time SR and NR mouse between metabolism spectrum more also show the time dependence metabolic indicator that is associated with phenotypic variability.In SR mouse, the homaluria of lower acetate is observed after HFD is 7 days.Comparatively speaking, in SR mouse, the homaluria of higher sucrose is noticed in the identical time.Surprisingly, taurine after HF feeds 7 days with the positive correlation of SR mouse and after 60 days with SR mouse negative correlation.The feature of the urine metabolism spectrum of HFD SR mouse after 60 days is also creatine, glycocyamine salt, tartrate, hippurate, and the increase of hydroxyphenyl acetoglycocoll.Interestingly, be characterized by trimethylamine-N-oxide and the isovaleryl glycocoll of the qualitative candidate markers of DIO, being also accredited as is the stable candidate markers of resisting obesity phenotype.These results point out that the leucine kalabolism that occurs in mitochondria and beta-oxidation are by strongly affecting of feeding of HF and its specific regulatory control may contribute to fat outbreak.
The homaluria graphic HF of the pointing out mouse of several metabolin and the specific of SR mouse Mitochondria metabolism go regulation and control
The regulation and control of the mouse Mitochondria metabolism that HFD feeds are studied further under the help of the univariate data method (see method) of supplementing.Beta-oxidation intermediate: the mouse fed than LF in the urine of the mouse that the homaluria of hexanoyl glycocoll, carnitine and fatty acyl carnitine is fed at HF as one man increases, the increase of fatty acid overflow and the activation of beta-oxidation in this indication wire plastochondria.After HFD feeds, the end-product (2PY, 4PY) of nicotinamide adenine dinucleotide approach also constantly increases in mouse retention, the rise of this prompting beta-oxidation and Pexoxisome proliferator.Integration confirms the catabolic intermediate of leucine, valine, isoleucine and BCAA (isovaleryl glycocoll, α-one-β methylvaleric acid and α-one valeric acid) in the mouse fed at HF significantly and as one man increase, support the hypothesis of the catabolic rise of BCAA that HFD is associated.Partly modulated in the mouse that Krebs circulation is also fed at HF, because constant rising compared with the mouse fed with LF in the HF urine of mouse of feeding, the short-term urine that we observed succinate in mouse after HFD is 7 days increases.These results support hypothesis, and namely valine and isoleucine kalabolism raise, induced synthesis succinyl-CoA and the following Krebs intercycle thing of generation.Surprisingly, in the mouse that other Krebs intercycle things (citrate, aconitase, α-ketoglutaric acid) are fed at LF with HF and non-significant is different, acetyl-CoA is produced in prompting leucine kalabolism and beta-oxidation, and Krebs circulation is separated.Concrete metabolic regulation can make the flow of acetyl-CoA turn to towards other metabolic pathways.Especially, the vinylacetyl Glycine Levels prompting acetyl-CoA increased in the urine of the mouse that HF feeds can towards acetoacetyl-CoA reorientation, and described acetoacetyl-CoA is associated with the formation of butyric acid metabolism and vinylacetyl glycocoll.The rise of these results verifications HFD inducing mitochondrial oxidisability approach and Krebs circulation, this may cause the increase of energy production.
Univariate data also enables us to understand better beta-oxidation under the background of phenotypic variability, association between BCAA kalabolism and Krebs circulation.In the urine of the integration display NR mouse of BCAA kalabolism intermediate only isovaleryl glycocoll than SR mouse or LF mouse significantly higher, the fat mouse of prompting opposing only destruction catabolic with leucine is associated.In whole experimentation NR mouse urine in hexanoyl glycocoll significantly higher than SR mouse, but the homaluria of carnitine and fatty acyl carnitine remains unchanged.Therefore, although beta-oxidation seems influenced in NR mouse, it is consistent for being flowing between NR and SR mouse towards mitochondrial fatty acid.In addition, we observed the remarkable increase of vinylacetyl glycocoll in the urine of NR mouse, and prompting acetyl-CoA redirects towards butyric acid metabolism.Interestingly, after HFD is 7 days, the difference that between NR and SR mouse, Krebs circulation is active is not observed.60 days time, in the urine of SR mouse, succinate is significantly higher, highlights the rise of Krebs circulation.As previously observed, the homaluria of other Krebs intercycle things (citrate, α-ketoglutaric acid, aconitate) does not change between NR and SR mouse, supports the hypothesis of the specific regulatory control in Krebs circulation.Our result prompting is after long time-histories HFD, and the fat mouse of tendency is associated with the infringement of energetic supersession, and what described characteristic of damage was that Krebs circulates goes.The quick active of beta-oxidation in the mouse that opposing is fat, leucine kalabolism and butyric acid metabolism may be the protection mechanism for fatty acid overflow, and it makes it possible to maintain energy homeostasis.
Use metabolin urine concentration (as passed through
1measured by H NMR spectrum), from the change multiple of baseline (T0), with the ratio of UCre (as passed through
1measured by H NMR spectrum), evaluate outstanding metabolin and the relation of weightening finish.Emphasize increase weight based on to the short-term metabolism response prediction of diet challenge and individuality be layered as the ability (namely during T7) of NR or SR.Summarize correlation coefficient value in Table 1, report change multiple in table 2 simultaneously.In order to select more sane mark, the % averaged accuracies of " bag is outer " data is used to reduce as variable key character.By this way; can measure according to its weightening finish neurological susceptibility (NR and SR phenotype; Fig. 5) distinguish the variable of experimenter better, prompting hexanoyl glycocoll, isovaleryl glycocoll, TMAO and acetate are the most sane metabolic markers for experimenter being layered as NR or SR phenotype.
Claims (14)
1. biomarker, wherein said biomarker is trimethylamine-N-oxide.
2. trimethylamine-N-oxide as in urine for detecting and/or quantitatively resist the purposes of biomarker of the possibility of the weightening finish of high fat diet induction.
3. diagnose experimenter to resist the method for the possibility of the weightening finish of high fat diet induction, described method comprises
The level of the previous trimethylamine-N-oxide from the urine samples that experimenter to be tested obtains of-mensuration, and
-compare the trimethylamine-N-oxide level of experimenter and the reference point measured in advance,
Wherein the pre-reference point measured is based on the average trimethylamine-N-oxide level in urine in control population, and
Wherein than the pre-reference point measured, the trimethylamine-N-oxide level reduced in sample shows the possibility of the increase of the weightening finish of resisting high fat diet induction.
4. the method for claim 3, also comprises step
The level of at least one other biological mark of the group of hexanoyl glycocoll, isovaleryl glycocoll, leucine, isobutyrate, acetate, glycocyamine salt, sucrose, tartrate, hippuric acid and hydroxyphenyl acetoglycocoll composition is selected from-mensuration urine samples, and
-compare the level of the described at least one other biological mark of experimenter and the reference point measured in advance,
Wherein the pre-reference point measured is based on the average level of this at least one other biological mark in the urine samples of normal health control population, and
The level of the hexanoyl glycocoll wherein increased than the pre-reference point measured in urine samples, isovaleryl glycocoll, leucine, isobutyrate, acetate and/or the glycocyamine salt reduced, sucrose, tartrate, hippuric acid and/or hydroxyphenyl acetoglycocoll shows the possibility of the increase of the weightening finish of resisting high fat diet induction.
5. the method any one of claim 3 to 4, the level of the biomarker wherein in sample and in reference passes through
1h-NMR and/or mass spectrometric determination.
6. the method any one of claim 3 to 5, the possibility of wherein resisting the reduction of the weightening finish of high fat diet induction shows the possibility developing the illness be associated with overweight and/or obesity.
7. method according to claim 6, the illness be wherein associated with overweight and/or obesity is that cardiac metabolism disease and/or metabolism go.
8. the method any one of claim 3 to 7, described method is treated underweight, normal, overweight or implement in obese subjects.
9. the method any one of claim 3 to 8, wherein experimenter is people or companion animals such as cat or dog.
10. the method any one of claim 3 to 8, the possibility of wherein resisting the reduction of the weightening finish of high fat diet induction shows the specific activation lacking mitochondrial oxidation approach.
11. methods any one of claim 3 to 8, the possibility of wherein resisting the increase of the weightening finish of high fat diet induction shows the specific activation of mitochondrial oxidation approach.
12. methods any one of claim 10-11, wherein mitochondrial oxidation approach is selected from the group be made up of beta-oxidation, butyric acid metabolism and leucine kalabolism.
13. methods any one of claim 3 to 12, wherein experimenter be children and adolescents, young man and/or be in the people developing overweight or risk of obesity.
14. methods any one of claim 3 to 13, wherein said method be used for for the particular group design layering of experimenter diet or design personalized diet for specific experimenter.
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| CA2893620A1 (en) | 2012-12-04 | 2014-06-12 | Nestec S.A. | Isovalerylglycine as biomarker for the predisposition for weight gain and obesity |
| DK2979088T3 (en) | 2013-03-28 | 2018-08-13 | Nestec Sa | ALFA-KETO ISOVALATED AS A BIOMARKER OF PREBIOTIC EFFECTS FOR WEIGHT-INCREASING PREVENTION |
| WO2014154493A1 (en) | 2013-03-28 | 2014-10-02 | Nestec S.A. | Indoxyl sulfate as a biomarker of prebiotic efficacy for weight gain prevention |
| WO2018081175A1 (en) | 2016-10-24 | 2018-05-03 | Habit, Llc | System and method for implementing meal selection based on vitals, genotype, and phenotype |
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| US20060160237A1 (en) | 2004-12-06 | 2006-07-20 | Applera Corporation | Method of screening urine for organic acids |
| US7373256B2 (en) | 2005-04-19 | 2008-05-13 | Nicholson Jeremy K | Method for the identification of molecules and biomarkers using chemical, biochemical and biological data |
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| ES2633769T3 (en) | 2012-12-04 | 2017-09-25 | Nestec S.A. | Hexanoylglycine as a biomarker for predisposition to weight gain and obesity |
| CA2893620A1 (en) | 2012-12-04 | 2014-06-12 | Nestec S.A. | Isovalerylglycine as biomarker for the predisposition for weight gain and obesity |
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| CN107076753B (en) * | 2014-09-30 | 2019-01-18 | 深圳华大基因科技有限公司 | Specific biomarker composition for obese people and application thereof |
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| CA2893615A1 (en) | 2014-06-12 |
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